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Full-Text Articles in Physical Sciences and Mathematics
Cyclobutanone Inhibitors Of Diaminopimelate Desuccinylase (Dape) As Potential New Antibiotics, Thahani Shifna Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl Dr., Katherine Konczak, Megan Beulke, Janielle Javier, Ken W. Olsen, Daniel P. Becker Ph.D.
Cyclobutanone Inhibitors Of Diaminopimelate Desuccinylase (Dape) As Potential New Antibiotics, Thahani Shifna Habeeb Mohammad, Emma H. Kelley, Cory T. Reidl Dr., Katherine Konczak, Megan Beulke, Janielle Javier, Ken W. Olsen, Daniel P. Becker Ph.D.
Chemistry: Faculty Publications and Other Works
Based on our previous success in using cyclobutanone derivatives as enzyme inhibitors, we have designed and prepared a 37-member library of α-aminocyclobutanone amides and sulfonamides, screened for inhibition of the bacterial enzyme diaminopimelate desuccinylase (DapE), which is a promising antibiotic target, and identified several inhibitors with micromolar inhibitory potency. Molecular docking suggests binding of the deprotonated hydrate of the strained cyclobutanone, and thermal shift analysis with the most potent inhibitor (3y, IC50 = 23.1 µM) enabled determination of a Ki value of 10.2 +/− 0.26 µM and observed two separate Tm values for H. influenzae DapE (HiDapE).
Gcn5-Related N-Acetyltransferases (Gnats) With A Catalytic Serine Residue Can Play Ping-Pong Too, Jackson T. Baumgartner, Thahani S. Habeeb Mohammad, Mateusz P. Czub, Karolina A. Majorek, Xhulio Arolli, Cillian Variot, Madison Anonick, Wladek Minor, Miguel A. Ballicora, Daniel P. Becker Ph.D., Misty L. Kuhn
Gcn5-Related N-Acetyltransferases (Gnats) With A Catalytic Serine Residue Can Play Ping-Pong Too, Jackson T. Baumgartner, Thahani S. Habeeb Mohammad, Mateusz P. Czub, Karolina A. Majorek, Xhulio Arolli, Cillian Variot, Madison Anonick, Wladek Minor, Miguel A. Ballicora, Daniel P. Becker Ph.D., Misty L. Kuhn
Chemistry: Faculty Publications and Other Works
Enzymes in the Gcn5-related N-acetyltransferase (GNAT) superfamily are widespread and critically involved in multiple cellular processes ranging from antibiotic resistance to histone modification. While acetyl transfer is the most widely catalyzed reaction, recent studies have revealed that these enzymes are also capable of performing succinylation, condensation, decarboxylation, and methylcarbamoylation reactions. The canonical chemical mechanism attributed to GNATs is a general acid/base mechanism; however, mounting evidence has cast doubt on the applicability of this mechanism to all GNATs. This study shows that the Pseudomonas aeruginosa PA3944 enzyme uses a nucleophilic serine residue and a hybrid ping-pong mechanism for catalysis instead …